RU2558099C2 - Combined medication for treatment of arterial hypertension in patients with diabetes mellitus - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry and describes a peroral combined medication for the treatment of arterial hypertension in patients with diabetes mellitus. The medication is made in the form of a tablet. The combined tablet contains perindopril erbumine, amlodipine besylate, sorbitol, microcrystalline cellulose, sodium carboxymethyl starch, povidone, magnesium stearate in quantities, given in the invention formula.

EFFECT: combination of perindopril, amlodipine and sorbitol in the composition of one tablet provides enhancement of the therapeutic effect.

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Description

The present invention relates to medicine, in particular to the pharmaceutical industry, and describes a method of manufacturing a tablet having antihypertensive activity.

Arterial hypertension is the most common chronic disease that affects up to 20-30% of the world's adult population. According to the World Health Organization, about 40% of Russia's adult population suffers from this disease, and among the causes of premature mortality in the country's population, hypertension is in first place.

At the same time, according to official statistics in Russia, more than 2 million people suffer from diabetes. According to leading experts, this figure is significantly underestimated, and in fact, the number of patients with diabetes in Russia is 2-3 times higher than official statistics and can reach 7 million people.

Diabetes mellitus and arterial hypertension are two interconnected pathologies that have powerful mutually reinforcing damaging effects. Arterial hypertension in patients with diabetes mellitus occurs approximately 2 times more often than in the general population. The frequency of arterial hypertension among patients with diabetes varies from 20 to 60%, depending on the criteria used for high blood pressure and the type of diabetes.

The choice of antihypertensive drugs is of particular importance, since diabetes mellitus imposes a number of restrictions on the use of a particular drug. It is necessary to take into account the spectrum of its side effects, possible effects on carbohydrate and lipid metabolism, as well as the presence of concomitant vascular complications in the patient. Therefore, antihypertensive drugs in the treatment of patients with diabetes should meet increased requirements, namely:

- possess high antihypertensive activity with a minimum of side effects;

- not violate carbohydrate and lipid metabolism;

- have a cardioprotective and nephroprotective effect;

- not worsen the course of other (non-vascular) complications of diabetes.

A dosage form for the treatment of arterial hypertension and cardiovascular diseases is known, comprising a composition of an angiotensin-converting enzyme inhibitor and a cardioselective beta-blocker, consisting of amlodipine and atenolol (RF Patent No. 2188636, patent holder F. Dr. Reddice Laboratory LTD.) In the proportions: atenolol - 25-100 mg, amlodipine besilate - 3-15 mg.

A stable drug composition with antihypertensive effect is also known (RF Patent No. 2341254, patent holder of ZAO Medimex), which is a composition comprising biso-prolol or metoprolol, or atenolol (beta-blocker), indapamide (diuretic), enalapril maleate ( angiotensin-converting enzyme) and vinpocetine.

The above antihypertensive pharmaceutical compositions are not recommended for use by patients with diabetes mellitus. Current recommendations limit the use of beta-blockers as first-line drugs in patients with arterial hypertension with multiple metabolic risk factors, including abdominal obesity, impaired glucose tolerance. The use of beta-blockers is not recommended for patients with insulin-dependent diabetes mellitus with frequent hypo- and hyperglycemia, as well as for patients with impaired recognition of hypoglycemic conditions (due to the development of autonomic neuropathy). Subjective sensations of developing hypoglycemia are often associated with activation of adrenergic receptors and blockade of the latter can lead to the development of coma without subjective precursors (Shestakova M.V. Arterial hypertension and diabetes mellitus: development mechanisms and treatment tactics / Diabetes mellitus. 1999. N3. S.19- 23).

In addition, a pharmaceutical composition is known (European patent EP No. 2162434, RF No. 2188636, publ. March 17, 2010) containing 3.34 mg of perindopril and 5 mg of amlodipine.

In the compositions indicated in the patent of the Russian Federation No. 2188636 and patent EP 2162434, lactose (anhydrous or monohydrate) is present in a significant amount by weight of the drug as an auxiliary substance, which is undesirable when choosing a drug for patients with diabetes mellitus, since this substance affects carbohydrate and lipid metabolism and blood sugar of the patient. In addition, restrictions on the use of lactose can be caused by intolerance to the latter. The frequency of constitutional lactose intolerance in Russia is 16-18% (Belmer S.V., Mukhina Yu.G., Chubarova A.I., Geraskina V.P., Gasilina T.V. Lactose intolerance in children and adults / Attending Doctor No. 1, 2005).

The technical task of the present invention is the creation of a new combined pharmaceutical composition having a hypotensive effect, which allows it to be used for the treatment of patients with diabetes mellitus and with a reduction in possible side effects for this group of patients.

A reduction in the possible side effects of the combination of perindopril and amlodipine is indicated by the PRORIV study. It was found that an increase in blood pressure-lowering effects when using this combination is accompanied by a decrease in the frequency of undesirable reactions, in particular leg edema, characteristic of calcium dihydropyridine antagonists. The study noted a significantly lower incidence of edema of the lower extremities when taking a fixed combination of perindopril / amlodipine (about 10%) compared with the same indicator in studies such as “VALUE” or “PREVENT” (about 30 and 40%, respectively). Edema was small and in most cases did not require not only the abolition of treatment, but also the dose adjustment of amlodipine. There is evidence that the cough associated with taking ACE inhibitors is also weakened by calcium antagonists, including amlodipine [Uncontrolled arterial hypertension - new possibilities in solving the problem of increasing the effectiveness of treatment / Yu.A. Karpov, A.D. Deev; Cardiology. - 2012. - No. 2. - p. 34, para. 1. CARDIOLOGY, 2012, No. 2].

According to the United Kingdom Prospective Diabetes Study (6th report), slow calcium channel blockers are among the drugs of choice for antihypertensive therapy in patients with diabetes (UKPDS Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38) // Brit. Med. J. - 1998 .-- Vol. 317. - P.703-713). Slow calcium channel blockers (calcium antagonists) do not adversely affect carbohydrate and lipid metabolism (metabolically neutral). They are widely used to treat arterial hypertension, so they can be used without concern and with great effectiveness in patients with arterial hypertension with diabetes mellitus. In addition to other advantages of slow calcium channel blockers, their renoprotective effect, mediated by the normalization of intracavitary hemodynamics, should be noted. Particularly effective in the treatment of arterial hypertension in diabetes mellitus are prolonged forms of dihydropyridine blockers of slow calcium channels, since they do not cause an increase in blood glucose in patients with diabetes mellitus and do not have a negative effect on the lipid profile of blood plasma, while having a good hypotensive effect. Amlodipine has the most lasting effect of all dihydropyridine blockers of slow calcium channels, its half-life reaches 35-45 hours.

In 20-60% of patients with diabetes mellitus, monotherapy even with the most powerful drugs is not able to stabilize blood pressure at the required level. In this case, to achieve this goal, the combination of several antihypertensive drugs of various groups is indicated. The most effective combinations of drugs in the treatment of hypertension in diabetes mellitus include a combination of an angiotensin-converting enzyme inhibitor and a diuretic, an angiotensin-converting enzyme inhibitor and a slow calcium channel blocker (Preobrazhensky D.V., Sidorenko B.A. Arterial hypertension in diabetes mellitus / Russian medical journal. 340-344).

According to the present invention, a solid pharmaceutical composition for oral administration has been developed which has the following composition:

- as a substance belonging to the blockers of slow calcium channels of the dihydropyridine class, amlodipine besylate is used;

- as a substance related to angiotensin-converting enzyme inhibitors, perindopril erbumin is used;

- sorbitol is used as the target additive, which is at least one structure-forming agent.

A similar combination of drugs from the prior art could not be identified.

The inventive composition is found experimentally, it is optimal and allows to obtain a technical result that is appropriate for the task: a pharmaceutical composition in the form of dosage forms of a tablet containing at least two active active ingredients to enhance the therapeutic effect, having a shelf life of at least 3 years and suitable for treatment arterial hypertension in patients with diabetes mellitus. The combination of an angiotensin-converting enzyme inhibitor (perindopril erbumin) with slow calcium channel blockers of the dihydropyridine class (amlodipine bezylate) causes a synergism of their hypotensive effect, and the content of sorbitol as a structure-forming agent with a diuretic effect enhances the hypotensive effect of N. (D) Ya.A., Morskaya ND, Yakhnitsa TV Prerequisites for the use of hyperosmolar sorbitol infusion solution in patients with decompensated chronic pulmonary heart / Ukrainian Pulmonary Journal. 2003. No. 1).

The therapeutic and synergistic effect of the combination of perindopril and amlodipine is enhanced by the data of the aforementioned PRORIV study, which noted the results of a secondary analysis of the EUROPA study, which showed a synergistic increase in the protective effects of perindopril in reducing the risk of cardiovascular complications and cardiovascular mortality in patients with a stable form of coronary heart disease with the simultaneous use of calcium antagonists [Uncontrolled hypertension - new possibilities in solving the problem of increasing the effectiveness of treatment / Yu.A. Karpov, A.D. Deev; Cardiology. - 2012. - No. 2. - p. 34, para. 3. CARDIOLOGY, 2012, No. 2].

An additional agent used as a filler in the invention is sorbitol. Sorbitol is not toxic, has a masking sweet taste, at the same time without causing rapid changes in the amount of sugar in the blood, and does not provoke additional production of insulin by the pancreas. Being a caloric sugar substitute, sorbitol is absorbed from the gastrointestinal tract, practically without affecting blood glucose, which allows the drug to be used for the treatment of patients with diabetes mellitus having a combined pathology of the hepatobiliary system. Sorbitol has a choleretic, detoxifying, laxative effect (Russian Medicines Radar Register of Medicines. Encyclopedia of Medicines. - 14th edition / Ed. G. Vyshkovsky. - M.: Radar. - 2006, 2005). In addition, in this combination, sorbitol has a diuretic effect. Diuresis, as is known to experts in the field of cardiology, is indicated in the treatment of arterial hypertension.

Most preferred is the following content of components in wt.%:

Components wt.% Perindopril erbumin 4.0 Amlodipine Besilate 3.47 (in terms of amlodipine base) 2,5 Sorbitol 75.03 Microcrystalline cellulose 10.0 Sodium carboxymethyl starch 4.0 Povidone 2,5 Magnesium stearate 1,0 Total 100.0

A specific variant of the formulation of the claimed composition is the following composition:

Components mg Perindopril erbumin 8.00 Amlodipine Besilate 6.94 (in terms of amlodipine base) 5,0 Sorbitol 150.06 Microcrystalline cellulose 20.00 Sodium carboxymethyl starch 8.00 Povidone 5.00 Magnesium stearate 2.00 Total 200,0

An additional diuretic effect in this combination, due to the inclusion of sorbitol as a filler, is confirmed by the experimental data given below.

Chronic experiments were carried out on 40 white outbred laboratory rats of both sexes, weighing 180-220 g, which were divided by lot into 4 groups in each of 10 animals:

Group 1 - control, received once intragastrically using a special device 3% water load relative to the body weight of the animal;

Group 2 - experimental, receiving once intragastrically sorbitol at a dose of 21 mg / kg against a background of 3% water load. The dose was taken similarly to the content of sorbitol in the claimed medicinal product (hereinafter “the Invention”) on sorbitol, namely 150 mg in 1 tablet per 70 kg of weight (average human weight), therefore, 2.1 mg / kg. This dose was increased 10 times due to the fact that rodents have a reduced sensitivity to most pharmacological agents in comparison with humans. So a dose of 21 mg / kg was obtained;

3 group - experimental, received once intragastrically claimed drug "Invention" of complex composition based on sorbitol at a dose of 29 mg / kg against a background of 3% water load. The dose calculation was carried out as follows. I took 1 tablet of 200 mg (perindopril 8 mg, amlodipine 7 mg, sorbitol 150 mg and excipients) per 70 kg of weight (average human weight), therefore, 2.9 mg / kg. The dose received was multiplied by 10, as rodents have a reduced sensitivity to a number of drugs in comparison with humans. Thus, a dose of 29 mg / kg was obtained. Moreover, the dose of sorbitol in the composition of this drug was 21 mg / kg;

4 group - experimental, received once intragastric drug "Invention" on lactose at a dose of 29 mg / kg against a background of 3% water load. The dose calculation was carried out as follows. 1 tablet was taken 200 mg (perindopril 8 mg, amlodipine 7 mg, lactose 150 mg and excipients) per 70 kg of weight (average human weight), therefore, 2.9 mg / kg. The dose received was multiplied by 10, as rodents have a reduced sensitivity to a number of drugs in comparison with humans. Thus, a dose of 29 mg / kg was obtained. Moreover, the dose of lactose in the composition of this drug was 21 mg / kg.

Before the introduction of the preparations, working solutions were prepared in distilled water. So a sample of sorbitol weighing 63 mg (which corresponds to 3 kg of live weight of animals) was uniformly mixed in 90 ml of distilled water (which corresponds to 3% water load per 3 kg of animal weight). A tablet of the inventive combined drug “Invention” on 200 mg sorbitol (corresponding to 7 kg of live weight of animals) was crushed and uniformly mixed in 210 ml of distilled water (which corresponds to 3% water load per 7 kg of animal weight). A tablet of the inventive combined drug “Invention” on lactose weighing 200 mg (which corresponds to 7 kg of live weight of animals) was crushed and uniformly mixed in 210 ml of distilled water (which corresponds to 3% water load per 7 kg of animal weight). Working solutions were administered to the corresponding groups of animals in a volume of 3% of the animal body weight, for example, 6 ml per 200 g of animal weight, 6.3 ml per 210 g, 6.6 ml per 220 g.

After drug administration and water loading, the animals were placed in metabolic cages for 4 hours, after which diuresis, sodium urease and potassium urine was determined (by flame photometry on a flame analyzer of the PAZh-1 liquid) and creatininuresis (by colorimetric method on a KFK-3 photocolorimeter).

Animal experiments were carried out in accordance with the requirements of the European Convention for the Protection of Vertebrate Animals.

Statistical processing of the obtained experimental results was carried out using the Microsoft Excel 2010 and Statistica 8.0 programs according to the Mann-Whitney criterion.

As a result of the experiment, it was found that sorbitol with a single intragastric administration at a dose of 21 mg / kg of animal weight against a background of 3% water load affects water-salt metabolism, increasing kidney excretion of water in experimental animals (group 2) compared with the control from 2.84 ± 0.10 ml / 4 h to 3.70 ± 0.16 ml / 4 h (30%, p <0.01), sodium from 297.80 ± 14.76 μmol / 4 h to 407.99 ± 43.17 μmol / 4 h (by 37%, p <0.05), potassium from 94.60 ± 4.14 μmol / 4 h to 131.10 ± 5.28 μmol / 4 h (on 39%, p <0.01), creatinine from 0.65 ± 0.10 mg / 4 h to 1.11 ± 0.15 mg / 4 h (71%, p <0.05) for 4 hours of experiment (Table 1). Which indirectly indicates that diuresis increased both due to an increase in glomerular filtration (a significant increase in creatininuresis) and due to a decrease in tubular reabsorption (a significant increase in natriuresis). Therefore, sorbitol in a selected dose has a diuretic effect.

With a single intragastric administration of the claimed drug “Invention” on sorbitol at a dose of 29 mg / kg (the dose of sorbitol in the composition of this drug was 21 mg / kg), an increase in diuresis was observed in experimental animals (group 3) compared with the control from 2, 84 ± 0.10 ml / 4 h to 3.41 ± 0.13 ml / 4 h (20%, p <0.01), sodium urea from 297.80 ± 14.76 μmol / 4 h to 399.15 ± 39.56 μmol / 4 h (30%, p <0.05), while creatinures decreased from 0.65 ± 0.10 mg / 4 h to 0.28 ± 0.07 mg / 4 h (at 57%, p <0.05) for 4 hours of the experiment (Table 1). These data indicate that diuresis increased solely due to a decrease in tubular reabsorption (a significant increase in natriuresis). Glomerular filtration was reduced (a significant decrease in creatininuresis) - this can be explained by the fact that the claimed drug “Invention” on sorbitol is combined and contains not only the diuretic component sorbitol, but also 2 antihypertensive components, perindopril and amlodipine. And antihypertensive drugs naturally reduce glomerular filtration by reducing systemic and local blood pressure. Therefore, the claimed combination drug "Invention" on sorbitol has a diuretic effect.

At the same time, a single intragastric administration of the combined drug “Invention” on lactose at a dose of 29 mg / kg (the lactose dose in this preparation was 21 mg / kg) of a significant change in renal excretion of water in experimental animals (group 4) in relation to the control, it did not cause, however, it contributed to a significant decrease in natriuresis from 297.80 ± 14.76 μmol / 4 h to 82.05 ± 9.89 μmol / 4 h (by 72%, p <0.01), potassium from 94.60 ± 4.14 μmol / 4 h to 50.74 ± 5.31 μmol / 4 h (47%, p <0.01), creatinose from 0.65 ± 0.10 mg / 4 h to 0.32 ± 0.07 mg / 4 h (at 51%, p <0.05) after 4 hours of exposure Note (Table 1). Therefore, this drug does not have diuretic activity.

It was also of interest to compare the effect on the excretory function of the kidneys of rats of two combined drugs: the inventive drug “Invention” on sorbitol and the drug “Invention” on lactose. In the course of studies, it was found that the “Invention” on sorbitol compared with the “Invention” on lactose significantly increases the following indicators of the excretory function of the kidneys: diuresis - by 32%, natriuresis - by 386%, potassium uresis - 113% in 4 hours of experiment ( Table 2).

The protocols of the chronic experiment are presented in tables 3-6. Thus, as a result of the experiment, it was found that the claimed drug "Invention" on sorbitol in diuretic and saluretic activity is close to sorbitol in a similar dose and exceeds the drug "Invention" on lactose.

The inventive combination drug for the treatment of hypertension in patients with diabetes mellitus can be made as follows.

Weighted sorbitol, perindopril erbumin, amlodipine besilate, microcrystalline cellulose, part of sodium carboxymethyl starch is mixed in a centrifugal paddle mixer. The resulting mixture is granulated in the fluidized bed of the dryer - granulator with an aqueous solution of povidone, then dried to the required residual moisture and calibrated. The calibrated granulate is dusted with magnesium stearate and the remainder of sodium carboxymethyl starch. The powdered mixture is tabletted on a rotary press.

The content of active substances in the tablet is 7.5%. Microcrystalline cellulose, which is most often used in the production of solid dosage forms, was selected as fillers, and, in order to achieve a technical result of the invention, sorbitol was used as filler, the combination of which allows one to obtain a strong tablet with a short disintegration time. In order to improve the bioavailability of the active substances, a disintegrant - carboxymethyl - sodium starch was introduced. For a uniform distribution of a relatively small amount of substances throughout the volume of the mixture, the components are mixed and sieved in dry form. Then, to improve the flowability of the tablet mass and its compressibility, to prevent stratification of the multicomponent mixture during tabletting, to achieve the necessary antifriction properties, on the basis of the work carried out, the optimal method for the industrial production of the mixture was chosen for this preparation - wet granulation with an aqueous solution of povidone in granulator dryers, followed by calibration, drying and dusting.

Studies have shown that obtaining a product by direct compression does not allow to obtain a stable result for the main parameters of the tablets: uniformity of dosage and strength. Tableting is carried out on rotational tablet machines, widely used in the pharmaceutical industry, the pressure in which gradually increases, which ensures soft and uniform pressing of the tablets.

Claims (1)

Combined drug for the treatment of arterial hypertension in patients with diabetes mellitus, including an effective amount of perindopril or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt, sorbitol, microcrystalline cellulose, sodium carboxymethyl starch, povidone, magnesium stearate with the content of components in wt.% And the amount of components in wt.% And the amount of components mg: